An Australian trial shows replacing methotrexate with post-transplant cyclophosphamide and cyclosporin slashes GVHD risk and extends relapse-free survival after matched related donor transplants.
A dual graft-versus-host disease (GVHD) prophylaxis regimen combining post-transplant cyclophosphamide with cyclosporin significantly prolonged GVHD-free, relapse-free survival compared with the long-standing cyclosporin–methotrexate combination, according to Australian researchers.
The benefit was seen in patients receiving allogeneic peripheral-blood stem-cell transplants from matched related donors.
Results from the phase 3 Australasian Leukaemia and Lymphoma Group (ALLG) BM12 CAST trial, reported in the New England Journal of Medicine, show median GVHD-free, relapse-free survival was 26.2 months in the experimental arm versus 6.4 months in the standard-prophylaxis group (HR 0.42; 95% CI, 0.27–0.66; P<0.001).
At three years, survival free from GVHD, relapse or death was 49% with cyclophosphamide–cyclosporin compared with 14% with standard therapy.
Led by Australasian Leukaemia and Lymphoma Group member Professor David Curtis from the Australian Centre for Blood Diseases (Alfred Hospital & Monash University), the BM12 CAST trial took place at eight Australian and New Zealand hospitals.
The trial enrolled 134 adults with high-risk haematological malignancies undergoing myeloablative or reduced-intensity conditioning. Patients were randomised to either the experimental dual regimen or the conventional calcineurin inhibitor-antimetabolite approach.
Severe acute GVHD (grade III–IV) at three months occurred in 3% of the experimental group versus 10% of the standard group, while two-year overall survival rates were 83% and 71%, respectively. Serious adverse events within the first 100 days were comparable.
Professor Curtis, who presented the findings at the European Haematology Association Congress 2025 in Milan, said: “This new treatment triples the chances of a patient being alive, healthy and free of GVHD three years after their stem cell transplant”.
Around 600 people undergo blood stem cell transplants each year in Australia and New Zealand, with about 150 developing acute or chronic GVHD.
The authors said the survival advantage appeared to be driven by a lower incidence of both acute and chronic GVHD, particularly severe grades linked to long-term complications and mortality. Relapse risk was not increased, consistent with previous reports on post-transplant cyclophosphamide.
They noted no prior randomised trials had compared post-transplant cyclophosphamide–based regimens with and without an antimetabolite, but retrospective data suggested omitting mycophenolate mofetil reduced acute GVHD. The new regimen also avoids gastrointestinal and infectious complications associated with the antimetabolite.
Unlike the BMT CTN 1703 trial – which reported higher organ-failure deaths with cyclophosphamide-tacrolimus-mycophenolate mofetil – the BM12 CAST trial found no increased risk of non-relapse death, ICU admission or CMV infection with the experimental regimen.
The researchers said their findings had the potential to change clinical practice, particularly in low-resource centres and those not using antithymocyte globulin.
“First, application of our experimental-prophylaxis regimen would simplify treatment, and our results are directly relevant to SCT from matched related donors, the preferred donor source,” they wrote.
“Second, we found benefits for patients undergoing myeloablative conditioning, which is used whenever possible for high-risk blood cancers. Before our trial, data from randomised trials on the use of post-transplantation cyclophosphamide-based GVHD prophylaxis in the context of myeloablative conditioning had been lacking.
“Third, we found that post-transplantation cyclophosphamide can effectively replace mycophenolate mofetil, a drug that is associated with substantial early post-transplantation complications.
“Finally, our trial showed a favourable safety profile and significantly higher GVHD-free, relapse-free survival with experimental prophylaxis than with standard prophylaxis, with a lower incidence of the most severe grades of GVHD, which cause death and long-term complications.”
